Targeted delivery of neural progenitor cell-derived extracellular vesicles for anti-inflammation after cerebral ischemia.
Targeted delivery of neural progenitor cell-derived extracellular vesicles for anti-inflammation after cerebral ischemia.
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靶向递送神经祖细胞来源的细胞外囊泡用于脑缺血后的抗炎作用。
作者：
Tian T;Cao L;He C;Ye Q;Liang R;You W;Zhang H;Wu J;Ye J;Tannous BA;Gao J
缺血性中风仍然是死亡的主要原因，抗炎策略对于预防再灌注期间的重大脑损伤具有很大的希望。在过去的十年中，干细胞衍生的细胞外囊泡（EV）已成为免疫调节中的新型治疗效应物。然而，由于未修饰的EV的靶向性差，将EV静脉内递送到缺血性脑中仍然是一个挑战，并且干细胞衍生的EV的大规模生产的成本阻碍了它们的临床应用。方法：从人神经前体细胞系中分离EV，并在体外验证其抗炎作用。为了将靶向配体连接到EV上，我们产生了一种重组融合蛋白，其含有与乳凝集素（C1 C2）的磷脂酰丝氨酸（PS）结合结构域融合的甘氨酸-天冬氨酸（RGD）-4C肽（ACDCRGDCFC），所述乳凝集素（C1 C2）容易地自缔合到EV膜上。随后，在大脑中动脉闭塞（MCAO）小鼠模型中，通过尾静脉静脉内注射RGD-C1 C2结合的EV（RGD-EV），然后进行荧光成像并评估促炎细胞因子表达和小胶质细胞活化。结果：神经前体细胞来源的EV具有内在的抗炎活性。RGD-EV在静脉给药后靶向缺血脑的病变区域，并导致对炎症反应的强烈抑制。此外，RNA测序揭示了包装在EV中的一组7种miRNA抑制MAPK，这是一种炎症相关途径。结论：这些结果指出了一个快速和简单的策略，以产生靶向EV，并提出了一个潜在的治疗缺血性中风的药物。
Ischemic stroke remains a major cause of death, and anti-inflammatory strategies hold great promise for preventing major brain injury during reperfusion. In the past decade, stem cell-derived extracellular vesicles (EVs) have emerged as novel therapeutic effectors in immune modulation. However, the intravenous delivery of EVs into the ischemic brain remains a challenge due to poor targeting of unmodified EVs, and the costs of large-scale production of stem cell-derived EVs hinder their clinical application. Methods: EVs were isolated from a human neural progenitor cell line, and their anti-inflammatory effects were verified in vitro. To attach targeting ligands onto EVs, we generated a recombinant fusion protein containing the arginine-glycine-aspartic acid (RGD)-4C peptide (ACDCRGDCFC) fused to the phosphatidylserine (PS)-binding domains of lactadherin (C1C2), which readily self-associates onto the EV membrane. Subsequently, in a middle cerebral artery occlusion (MCAO) mouse model, the RGD-C1C2-bound EVs (RGD-EV) were intravenously injected through the tail vein, followed by fluorescence imaging and assessment of proinflammatory cytokines expression and microglia activation. Results: The neural progenitor cell-derived EVs showed intrinsic anti-inflammatory activity. The RGD-EV targeted the lesion region of the ischemic brain after intravenous administration, and resulted in a strong suppression of the inflammatory response. Furthermore, RNA sequencing revealed a set of 7 miRNAs packaged in the EVs inhibited MAPK, an inflammation related pathway. Conclusion: These results point to a rapid and easy strategy to produce targeting EVs and suggest a potential therapeutic agent for ischemic stroke.
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影响因子：
46.9
作者：
Alvarez-Erviti, Lydia;Seow, Yiqi;Wood, Matthew J. A.
通讯作者：
Wood, Matthew J. A.
在两个人类神经干细胞系中神经元生理反应性的差异发展。
影响因子：
2.4
作者：
Donato, Roberta;Miljan, Erik A.;Hines, Susan J.;Aouabdi, Sihem;Pollock, Kenneth;Patel, Sara;Edwards, Frances A.;Sinden, John D.
通讯作者：
Sinden, John D.
影响因子：
48
作者：
Fisher, Marc;Saver, Jeffrey L.
通讯作者：
Saver, Jeffrey L.
影响因子：
56.9
作者：
BROOKS, PC;CLARK, RAF;CHERESH, DA
通讯作者：
CHERESH, DA
影响因子：
6.7
作者：
Kooijmans SAA ;Gitz-Francois JJJM ;Schiffelers RM ;Vader P
通讯作者：
Vader P